Reaction of benzohydroximinoyl chlorides and β -(Trifluoromethyl)-acetylenic esters: Synthesis of regioisomeric (Trifluoromethyl)-isoxazolecarboxylate esters and oxime addition products

Article abstract of DOI:10.1002/jhet.5570400404

The triethylamine induced reaction of benzohydroximinoyl chlorides, precursors of nitrile oxides, with β-trifluoromethylacetylenic esters gives rise to three products: 5-trifluoromethyl-4-isoxozolecarboxylate esters, regioisomeric 4-trifluoromethyl-5-isox

Full text of DOI:10.1002/jhet.5570400404

Jul-Aug 2003
575
Reaction of Benzohydroximinoyl Chlorides and b-(Trifluoromethyl)-
acetylenic Esters: Synthesis of Regioisomeric (Trifluoromethyl)-
isoxazolecarboxylate Esters and Oxime Addition Products
Bruce C. Hamper* and Kindrick L. Leschinsky
Monsanto Company, AG Sector, 800 N. Lindbergh Blvd.,
St. Louis, MO 63167, USA
Received February 5, 2003
The triethylamine induced reaction of benzohydroximinoyl chlorides, precursors of nitrile oxides, with
b-trifluoromethylacetylenic esters gives rise to three products: 5-trifluoromethyl-4-isoxozolecarboxylate
esters, regioisomeric 4-trifluoromethyl-5-isoxazolecarboxylate esters and an unexpected oxime 1,4-addition
adduct. Product distribution is rationalized in terms of two competing reaction modes, either 1,4 addition of
the oxime anion to the acetylenic ester or formation of the nitrile oxide followed by 1,3-dipolar cycloaddi-
tion. Anionic 1,4-addition of the oximinoyl chloride to the acetylenic ester is preferred at low temperatures,
while nitrile oxide formation followed by cycloaddition is preferred at temperatures above 0 °C.
Regioisomeric products from addition of nitrile oxides to various perfluoroalkylacetylenes are compared and
assigned by 13C NMR.
J. Heterocyclic Chem., 40, 575(2003).
Introduction.
minor products have not been previously isolated or char-
acterized [15,18]. A notable exception is the addition of 1-
aryl-3-trifluoromethylacetylenes to nitrile oxides which
gives 4-trifluoromethylisoxazoles as the major product
[19].
Haloalkyl and trifluoromethyl isoxazoles have been
reported as antiviral agents [1], anti-inflammatory agents
[2,3], tissue factor Xa inhibitors [4], immunosuppressents
[5], herbicides [6] and antifungal agents [7]. Often the
trifluoromethyl substituted isoxazoles are included along
with non-fluorinated analogs as patent examples of biolog-
ically active compounds. However, in some cases
trifluoromethylisoxazoles have been shown to have partic-
ularly enhanced activity and/or selectivity compared to
non-fluorinated analogs as in the case of anti-inflamma-
tory COX-2 inhibitors [2] and herbicidal protoporphyrin-9
oxidase inhibitors [8].
Trifluoromethylisoxazoles have been prepared by cyclo-
condensation of hydroxylamine and conjugated ynone [9],
b-diketones [10,11] or difluoroalkyl-2-iodoalkenes [12] or
by 1,3-dipolar cycloadditions of nitrile oxides and trifluo-
romethyl substituted dipolarophiles such as pyrrolidino-
acrylates [13], b-ketoesters [14] and acetylenic esters [15-
17]. The cyclocondensation routes provide 3- and 5-trifluo-
romethylisoxazoles depending on the conditions employed.
Linderman [9] was able to obtain 5-trifluoro-
methylisoxazole from hydroxylamine and trifluoromethyl-
acetylenic ketones under basic conditions, and the corre-
sponding 3-trifluoromethyl isomer under acidic conditions.
While the cyclocondensations typically provide 3,5-disub-
stituted isoxazoles, these products have been substituted in
the four position by alkylation of the lithium anion to pro-
vide trisubstituted 5-trifluoromethylisoxaozles [10].
Trisubstituted isoxazoles can be prepared directly by dipo-
lar cycloadditions, which give 5-trifluoromethyl isomers as
the major product from addition of nitrile oxides to
perfluoroalkyl substituted b-ketoesters, acetylenes and
acrylates. Small amounts (5 – 10%) of the regioisomeric
4-trifluoromethylisoxazoles have been proposed based on
the analysis of crude reaction mixtures, however these
In the course of investigating the biological activity of
isoxazolecarboxamides 6 [8], we needed to obtain various
isomers of the isoxazolecarboxylate ester precursors 3 for
preparation of regioisomeric analogs for structure-activity
relationship studies (Scheme 1). Carboxamide derivatives
6 of 3-aryl-5-perhaloalkyl-4-isoxazolecarboxylic acids
have been found to be potent inhibitors of protoporphyrin
IX oxidase [20]; the putative cause of herbicidal activity
observed in whole plant studies [21]. A detailed investiga-
tion of the reaction of benzohydroximinoyl chlorides 1 and
b-perfluoroalkylacetylenic esters 2 led to the identification
of both regioisomeric products 3 and 4, and the unexpected
observation of 'Michael type' or 1,4-addition product 5.

576
B. C. Hamper and K. L. Leschinsky
Vol. 40
This is to our knowledge the first report of nucleophilic
addition of the intermediate oxime to the dipolarophile in a
1,3-dipolar cycloaddition reaction.
At –70 °C (entry e) the formation of nitrile oxide is almost
completely suppressed and the oxime addition product 5 is
obtained as the major product. In a preparative run at
slightly higher temperature (entry d), oxime5 was isolated
in 51% yield and chloro-displacement product 9 in 5%
yield. Presumably, compound 9 arises from nucleophilic
addition of 1 to the hydroxyiminoyl chloride 5. The use of
the soluble base triethylamine is critical for formation of
the oxime addition products, since either two phase aque-
ous hydroxide or the absence of base (entries f, g) gave
only the dipolar cycloaddition products. Since hydroximi-
noyl chlorides are known to form nitrile oxides by thermal
decomposition even in the absence of base [22], we inves-
tigated neutral conditions in methylene chloride (entry g).
Although it required 5 days for 50% conversion, only the
expected isoxazole products were obtained. In practice,
the two phase aqueous hydroxide conditions (entry f),
which provided nearly instantaneous conversion to the
nitrile oxide intermediate, gave the best preparative route
towards the isoxazoles 3a and 4a without any measureable
amount of the oxime addition product.
Results and Discussion.
Our initial investigation of the reaction of benzohydrox-
iminoyl chloride 1 and acetylenic ester 2a in the presence
of triethylamine gave rise to three isolable products: the
5-(trifluoromethyl)isoxazole 3a, its expected regioisomer
4a and oxime addition adduct 5 (Scheme 2). The 5- and
19
4-position CF groups of 3a and 4a have distinctive
F
3
NMR resonances at -62.8 and -54.7 ppm, respectively,
which are consistent with the downfield shift previously
reported for 4-CF isoxazoles [19]. The corresponding CF
3
3
group of 5 appears at -69.6 ppm, which is significantly
upfield of the isoxazole isomers and makes identification of
the oxime addition product straightforward in the reaction
mixtures. All three components were separated by silica
chromatography from a multigram scale reaction to give
regioisomeric isoxazoles 3a (49%) and 4a (3%) and the
oxime 5 (8%). Mass spectral analysis demonstrated that
product 5 contains one chlorine atom and has a mass of 375
amu. Structural assignment is consistent with the acyclic
The results obtained for formation of both isoxazoles
and acyclic addition products are consistent with the
deprotonation of hydroximinoyl chloride 1 to give ion pair
7 which can either add to acetylenic ester 2a to give a
Michael addition adduct 5 or can lose HCl to give the
nitrile oxide 8 followed by the usual 1,3-dipolar
1
product, having a vinyl proton (6.03 ppm) in the H NMR.
13
The C NMR spectrum of 5 shows the olefinic carbons C2
and C3 at 105.9 ppm (q, J = 4 Hz) and 150.5 ppm (q, J = 35
Hz), respectively, and the oxime carbon at 144.8 ppm.
At room temperature and at 0 °C, the reaction of
hydroximinoylchloride with acetylene 2a in the presence
of triethylamine gave mixtures of the isoxazole regioiso-
mers 3a and 4a and oxime adduct 5 (Table 1, entries a,b).
Attempts to obtain more of the minor isomer 4a by lower-
ing the reaction temperature afforded increasingly greater
amounts of oxime addition products 5 and 9 (entries b-e).
cycloaddition products 3a and 4a. All three products are
stable to the reaction conditions and do not decompose or
interconvert in the presence of triethylamine. Temperature
studies indicate that in the absence of nitrile oxides, which
can react with the electron deficient acetylene 2a, only
Michael addition adducts would be obtained. To test this
idea, we considered investigating the addition of

Jul-Aug 2003
577
Reaction of Benzohydroximinoyl Chlorides and b-(Trifluoromethyl)acetylenic Esters
Table 1
Effect of Reaction Conditions on the Ratio of Regioisomeric Isoxazoles and Oxime Addition Products
Entry
Reaction Conditions[a]
Product Composition (%)[b]
3a
4a
5
9
a
b
c
d
e
f
Et N, 30 °C, 18 h
72
58(49)
29
19
10
20
15(3)
6
2
1
8
-
2
4
4(5)
2
-
-
3
Et N, 0 °C, 18 h
25(8)
61
75(51)
87
-
3
Et N, -17 °C, 18 h
3
Et N, -45 °C, 18 h
3
Et N, -70 °C, 18 h
3
aq. NaOH, 0 °C, 1 h
no base, RT, 5 days[c]
78(65)
92
22
8
g
-
[a] All reactions were run in methylene chloride using the listed base, time and temperature; [b] Percent composition was determined by a combination of
1
19
19
HPLC and integration of H and F NMR product resonances. Isolated yields are given in parenthesis; [c] 50% complete as determined by F NMR.
Table 2
benzaldoxime to acetylene in the presence of base. The
non-chlorinated oxime precursor would not be able to
form nitrile oxides and would be limited to the anionic 1,4-
addition reactions. However in agreement with reported
results [23], only benzonitrile was obtained on treatment of
benzaldoxime with base. Therefore we prepared acetophe-
none derivative 10, which on treatment of 2a gave nearly
quantitative yield of the oxime addition product 11
(Scheme 3). Similar results have been observed in the
addition of acetophenone oxime to dimethyl acetylene-
dicarboxylate and, under certain conditions, addition of
benzaldoxime to acetylenic esters [23,24]. In the presence
of base, carbethoxyhydroxyiminoyl chloride 12 gives an
electron deficient nitrile oxide, which does not react with
2a. The only products observed upon treatment of 12 with
the ethyl ester derivative of acetylene 2a are the furoxan 13
(from dimerization of the nitrile oxide) and Michael
addition adducts 14 and 15. The nitrile oxide from 12
undergoes cycloaddition under conditions of reverse elec-
tron demand and requires an electron rich dipolarophile.
Bravo, et. al. [14] has reported the cycloaddition of 12
Ratio of 1,3-Dipolar Cycloaddition Products Obtained from Acetylenes
2 and Hydroximinoyl Chloride 1
Compd.
R
R
Product Ratio (%)[a]
3
Reaction
Temp
1
2
4
a
b
c
d
e
f
g
h
i
CF
CF CF
CF Cl
CF H
CF
CF
CF
CH
H
CO CH
CO Et
CO CH
2
CO Et
H
CF
Ph
CO CH
CO CH
80(49)
79(38)
87(68)
85(76)
77(41)
(60)
20(3)
21(18)
13(5)
15(2)
23
0 °C
0 °C
RT[b]
RT
0 °C
RT
40 °C
0 °C
0 °C
3
2
3
2
3
2
2
3
2
2
3
3
3
-
33(11)[c]
1
72(61)[d]
3
99(83)[d]
28(9)[d]
3
2
3
3
2
[a] Product ratios were determined by a combination of HPLC and integra-
1
19
tion of product resonances by H and F NMR. Isolated yields are given
in parenthesis. Unless otherwise stated, Ar = 4-(trifluoromethyl)phenyl;
[b] Aqueous 50% NaOH was used as the base; [c] Furoxan 16 and oxadia-
zole 17 were 66% of the reaction product; [d] For entries h and i: Ar =
phenyl. Product composition and yields were obtained from ref. 27.
with CF substituted ketoesters as a route towards
3
5-trifluoromethylisoxazoles.
The reaction of acetylenic esters 2a-d with 1 gave the
5-perhaloalkylisoxazoles 3a-d as the major product and

578
B. C. Hamper and K. L. Leschinsky
Vol. 40
small amounts (2-18%) of the 4-perhaloisoxazoles 4a-d,
which were isolated and fully characterized (Table 2). As
seen previously with acetylene 2a, minor amounts of the
Michael addition adducts were also obtained for the
reactions with 2b-d; however, the reaction temperature
was controlled to suppress their formation. Other electron
deficient acetylenes 2e-g, which lack the ester functional-
ity, did not give rise to oxime addition products and the
isoxazoles 3e, 3f and 4g were isolated as the major prod-
ucts [25]. The more sterically hindered phenylacetylene 2g
afforded isoxazole 4g in only 33% yield and appreciable
amounts of furoxan 16 and oxadiazole 17 were obtained
(Scheme 4) [19]. Oxadiazoles have been previously
observed in the dimerization of nitrile oxides and are
suggested to be the product of a disproportionation reac-
tion between the initially formed oxadiazole-oxide and
excess nitrile oxide [26]. To eliminate any possible role of
the acetylene or its intermediates in the formation of oxa-
diazole 17, the reaction of hydroximinoyl chloride 1 with
triethylamine was carried out in the absence of acetylene
2g. In this case a nearly 1:1 ratio of furoxan 16 and
oxadiazole 17 was obtained, which eliminates the possibil-
ity of the acetylene playing a role in the formation of 17
and supports the previously reported disproportionation
reaction. The selectivity for formation of 3h and 4h
observed with non-fluorinated acetylene 2h under nearly
identical conditions to ours has been reported by Huisgen,
et. al. [27] and provides almost exclusive formation of the
4-isoxazolecarboxylate ester 3h over the regioisomer 4h
(99:1), whereas addition to methyl propiolate 2i affords
primarily the 5-isoxazolecarboxylate 4i (72%).
13
Analysis of C NMR is particularly useful for unam-
biguous assignment of the regiochemistry of perfluoro-
alkylisoxazoles 3 and 4 and can be effectively used even in
the absence of one of the two isomers (Table 3) [28]. The
CF substituted carbon of the isoxazole ring is readily
3
13
apparent in the C NMR due to the strong carbon-fluorine
two bond coupling ( J is 26-44 Hz). In a comparison of
the C NMR spectra of the two regioisomers, the CF
2
CF
13
3
substituted carbon (C5, 160.9 ppm) of 3a appears down-
field of the CF substituted carbon (C4, 113.4 ppm) of
3
regioisomer 4a. Chemical shift in the range of 140-160
ppm is characteristic of the C3 and C5 ring carbons of
isoxazoles, while the C4 carbon appears in the olefin
region (105-120 ppm) [14]. Therefore, all of the 4-perfluo-
roalkylisoxazoles 4a-d,g have C4 chemical shift of 106.5 -
2
119.0 ppm and J of 29-40 Hz. Likewise, the 5-perfluo-
CF
roalkylisoxazoles 3a-f have C5 chemical shifts of 158.8-
2
166.7 ppm and J of 26-44 Hz. The characteristic chem-
CF
ical shifts of the C4 versus C5 carbon, along with the
strong 2 bond C-F coupling, allows unambiguous assign-
ment of isoxazoles 3 and 4. This is particularly useful for
Table 3
13 19
1
Selected C, F and H NMR Resonances for Regioisomeric Isoxazoles 3 and 4 [a]
13
19
1
Compound
C NMR[b]
F NMR[c]
H NMR[d]
C3
C4
C5
3a
4a
3b
4b
3c
4c
3d
4d
3e
3f
159.7
155.9
159.4
155.4
159.9
159.8
159.8
156.1
112.6 (q, 2.5 Hz)
113.4 (q, 40 Hz)
115.5
111.1 (t, 30 Hz)
111.0
119.0 (t, 33 Hz)
112.3 (t, 3 Hz)
117.4 (t, 29 Hz)
103.6 (q, 2 Hz)
111.6 (qq, 41 Hz, 2 Hz)
106.5 (q, 38 Hz)
160.9 (q, 40 Hz)
160.7 (q, 3 Hz)
158.8 (t, 32 Hz)
161.8
163.8 (t, 36 Hz)
158.6 (t, 3 Hz)
166.7 (t, 26 Hz)
159.4 (t, 9 Hz)
160.1 (q, 43 Hz)
159.6 (qq, 44 Hz, 3 Hz)
160.7
-62.8
-54.7
-113.0 (q, 2F, 3 Hz)
-105.9 (q, 2F, 3 Hz)
-51.6
-45.6
-124.7
-115.2
-67.9
3.89[e]
4.07[e]
4.34 (q, 2H, 7 Hz)[f]
4.52 (q, 2H, 7 Hz)[f]
3.89[e]
4.07[e]
4.33 (q, 2H, 7 Hz)[f]
4.53 (q, 2H, 7 Hz)[f]
161.7
161.1 (q, 1.3 Hz)
171.9 (q, 8 Hz)
-62,0 -55.0
-53.2
4g
13
1
19
13
[a] Chemical shifts are expressed in ppm relative to TMS ( C and H nmr) and trichlorofluoromethane ( F nmr); [b] The C nmr resonances of the
19
three isoxazole ring carbon atoms. Two and/or three bond carbon-fluorine coupling along with the multiplet pattern is listed in parentheses; [c] F nmr
resonance of the isoxazole substituted perfluoroalkyl group. For compounds 3b and 4b, the J coupling is shown in parentheses; [d] H nmr resonance
3
1
FF
of the a -protons of the alkyl ester; [e] Methyl ester (R=H); [f] Ethyl ester (R=CH ).
3

Jul-Aug 2003
579
Reaction of Benzohydroximinoyl Chlorides and b-(Trifluoromethyl)acetylenic Esters
The mixture was heated to 250 °C to complete the thermolysis
and the acetylene collected in the dry ice trap. Vacuum distilla-
tion of the product afforded 6.22 g (84.6%) of a clear, colorless
oil: bp19 55-57 °C (lit.[33] bp40 60-62 °C); 1H NMR (CDCl3): d
7.41 (t, 2H, J=8 Hz); 7.50 (t, 1H, J=8 Hz), 7.57 (d, 2H, J=8 Hz);
the assignments of 3f and 4g in which only one isomer was
isolated from the reaction mixtures. As previously reported
19
by Meazza [19], an upfield F NMR shift was observed
for the fluorine resonances of 4-fluoroalkyl isoxozoles
compared with 5-fluoroalkyl isomers with each pair of
2
13C NMR (CDCl3): d 75.8 (q, C2, JCF=52 Hz), 86.7 (q, C3,
1
regioisomers 3a-d and 4a-d. The H NMR spectra of the
3JCF=7 Hz), 115.0 (q, CF3, 1JCF=257 Hz), 118.6 (q, C4, 4JCF=3
Hz), 128.7, 131.0, 132.5 (q, J=1.6 Hz); 19F NMR (CDCl3): d -
49.4 (s, 3F); IR (neat) 3010 (CH, str), 2200, 1290, 1130.
Anal. Calcd. for C9H5F3: C, 63.54; H, 2.96. Found: C, 63.47,
H, 2.98.
isoxazolecarboxylate esters exhibited a downfield shift for
the ester protons of 5-isoxazolecarboxylates (either the
methyl protons of 4a and 4c or the methylene protons of
4b and 4d) compared to the regioisomers 3a-d.
In summary, the reaction of benzohydroximinoyl chlo-
rides with b-perfluoroalkylacetylenic esters in the presence
of base gives rise to a mixture of products including trisub-
stituted isoxazole 3, its expected regioisomer 4, and
'Michael type'addition adducts 5 and 9. At low temperatures
using triethylamine as a base, the O-substituted oxime 5 is
the preferred product, whereas, at higher temperatures isox-
azole 3 is the major product. The observed products can be
rationalized by two competing mechanistic pathways invok-
ing a Michael addition for the formation of the oxime and
the more usual nitrile oxide intermediate for the formation
of isoxazoles. Unambiguous assignment of the isoxazole
regioisomers 3 and 4 can be determined by analysis of the
Formation of Dipolar Cycloaddition Products: Methyl
5-(Trifluoromethyl)-3-[4-(trifluoromethyl)phenyl]-4-isoxazole-
carboxylate (3a).
A solution of 1 (44.9 g, 0.20 mol) in 300 mL of CH2Cl2 was
cooled in a wet ice-acetone bath to –7 °C and treated at once with
2a (31.5 g, 0.21 mol). The stirred solution was treated dropwise
with triethylamine (29.5 mL, 0.21 mol) such that the reaction
temperature was maintained below –2 °C. After 90 minutes,
addition was complete and the reaction allowed to stir overnight.
The reaction mixture was washed with 1 N HCl and the organic
layer dried and concentrated in vacuo to afford 66.2 g of an
orange-yellow liquid. The reaction mixture was purified by silica
chromatography (10% CH2Cl2 in hexanes) to afford three frac-
tions; 33.4 g (49%) of 3a (k'=1.35), 6.2 g (8.3%) of 5 (k'=4.0) and
2.1 g (3.1%) of 4a (k'=4.8). The major component (first eluted
fraction) 3a crystallized on standing and was recrystallized from
cold pentane to afford a white, crystalline solid 3a: mp 49-50 °C;
1H NMR (CDCl3): d 3.89 (s, 3H), 7.74 (d, 2H, J=8 Hz), 7.82 (d,
13
C NMR and the two bond carbon-fluorine coupling.
EXPERIMENTAL
General Procedures.
3
2H, J=8 Hz); 13C NMR (CDCl3): d 53.1, 112.6 (C4, JCF = 2.5
1
1
Hz), 117.7 (CF3, JCF = 273 Hz), 124.0 (CF3, JCF = 273 Hz),
125.8 (3JCF = 4 Hz), 129.9, 130.3, 133.0 (C4', JCF = 34 Hz),
2
159.7 (C3), 160.9 (C5, 2JCF = 40 Hz), 162.3; 19F NMR (CDCl3):
d -62.8 (s), -63.0 (s); MS(EI) 339 (M+, 87), 320 (-F, 18), 308
(-OCH3, 27), 270 (-CF3, 100), 258 (30), 211 (40), 145 (CF3C6H4,
53), 59 (CO2CH3, 46); MS(CI) 340 (M+1, 100).
Anal. Calcd. for C13H7F6NO3: C, 46.03; H, 2.08; N, 4.13.
Found: C, 46.15; H, 2.10; N, 4.12.
All melting points were recorded on a Thomas-Hoover capil-
lary melting point apparatus and are uncorrected. NMR spectra
were obtained on a Bruker 360 MHz, a Varian EM-360, a Varian
XL-400 or an IBM-360. Proton and 13C resonances are reported
relative to internal tetramethylsilane in parts per million, whereas
19F resonances are reported relative to trichlorofluoromethane
using trifluorotoluene (-63.79 ppm) as an external coaxial stan-
dard. Electron impact and chemical ionization mass spectra were
recorded on a Finnigan 4535 spectrometer. Elemental analyses
were preformed by Analytical Microlabs, Inc. or by Midwest
Microlab. Reverse-phase HPLC analysis was performed with
250 mm X 0.46 mm i.d. columns containing a 5-um C18 ODS
bonded phase, using 0.1% aqueous TFA/acetonitrile mixtures as
the mobile phase. The 4-(trifluoromethyl)benzo-hydroximinoyl
chloride 1 was prepared from the benzaldehyde by a modification
of the known two-step procedure via the isolated oxime [8,29].
The acetylenic esters 2a-d and (3,3,3-trifluoro-1-propynyl)ben-
zene 2g were prepared by thermolysis of the corresponding acy-
lated phosphorane [30,31]. p-Trifluoromethylacetophenone
oxime 10 was prepared by the literature method [32].
Methyl 4-(Trifluoromethyl)-3-[4-(trifluoromethyl)phenyl]-5-
isoxazolecarboxylate (4a).
The most chromatographically retained material 4a was crys-
tallized from cold pentane to afford a white, crystalline solid 4a:
mp 34.0-34.5 °C; 1H NMR (CDCl3): d 4.07 (s, 3H), 7.73 (d, 2H,
J = 8 Hz), 7.77 (d, 2H, J = 8 Hz); 13C NMR (CDCl3) d 54.0,
2
1
113.4 (C4, JCF = 40 Hz), 120.5 (CF3, JCF = 269 Hz), 123.9
1
(CF3, JCF = 273 Hz), 125.9 (JCF = 4 Hz), 129.8 (JCF=3 Hz),
130.3, 133.0 (C4',2JCF=34 Hz), 155.9 (C3), 160.7 (C5, JCF
=
3
3 Hz), 160.9; 19F NMR (CDCl3) d -54.7, -63.0; MS(EI) 339 (M+,
31), 320 (-F, 6), 308 (-OCH3, 2), 280 (-CO2CH3, 100), 145
(CF3C6H4, 38).
Anal. Calcd. for C13H7F6NO3: C, 46.03; H, 2.08; N, 4.13.
Found: C, 46.13; H, 2.09; N, 4.08.
(3,3,3-Trifluoro-1-propynyl)benzene (2g).
Oxime Addition Products: Methyl 3-(((4-(trifluoromethyl)-
phenyl)chloromethylene)-amino)oxy-(4,4,4-trifluoro)butenoate (5).
By employing a previously described vacuum distillation
apparatus [30] equipped with a dry ice-acetone trap, 19.4 g
(43.2 mmol) of 1,1,1-trifluoro-3-phenyl-3-(triphenylphospho-
ranylidene)-2-propanone [31] was thermolyzed under reduced
pressure (2 Torr). Once the distillation pot reached 190 °C, the
solid phosphorane melted and formation of the acetylene began.
To a solution of 5.61 g (25.1 mmol) of 1 in 40 mL of CH2Cl2
was added 3.2 mL (25.3 mmol) of acetylene 2a. The mixture was
cooled in an acetonitrile/dry ice bath to -55°C and treated drop-
wise with 3.5 mL (25.1 mmol) of triethylamine such that the

580
B. C. Hamper and K. L. Leschinsky
Vol. 40
temperature was maintained below -45°C. The mixture was
allowed to stir overnight, washed with 1N HCl and the acid wash
extracted twice with CH2Cl2. The combined extracts were dried
and conc. in vacuo to afford a crude oil. Chromatographic purifi-
cation (silica, 2” x 22”, 30% CH2Cl2 in hexanes) afforded 4.83 g
(51.2%) of 5 and 0.75 g (5.3%) of 9 as a crystalline solid. The
first eluted chromatographic fraction 5 was obtained as an oil
which could be crystallized in cold pentane to afford a white
crystalline solid 5: mp 30-33°C; 1H NMR (CDCl3) d 3.72 (s,3H),
6.03 (s,1H), 7.69 (d,2H,J=8 Hz), 7.98 (d,2H,J=8 Hz); 13C NMR
(CDCl3) d 52.4, 105.9 (q, J = 4 Hz), 119.4 (CF3, J = 276 Hz),
123.8 (CF3, J = 271 Hz), 125.9 (q, J = 4 Hz), 128.3, 133.9 (q,
2JCF = 32 Hz), 134.5, 144.8, 150.5 (q, 2JCF = 35 Hz), 163.6; 19F
NMR (CDCl3) d -63.0(3F), -69.6(3F); MS(EI) 375(M+,6),
206(CF3C6H4CNCl,100), 145(CF3C6H4,75); MS(CI) 376
(M+1,100), 377 (12), 378 (28), 379 (4).
butynoate in 75 mL of CH2Cl2 at 30 °C was added dropwise
7.7 mL (55 mmol) of triethylamine. After stirring overnight, the
mixture was washed with 1 N HCl, dried and the solvent removed
to afford 14.2 g of a reddish oil. Chromatographic purification
(silica, 2” x 22”, 5% ethyl acetate in hexanes) afforded 3.0 g
(18.9 %) of a mixture (k', 3) of the two syn and anti isomers
which were not separable by silica gel chromatography and 2.23
g (38.7 %) (k', 4.8) of diethyl furoxandicarboxylate 13 [34]. The
mixture of isomers was purified by reverse phase chromatogra-
phy (C18, 21.2 mm i.d. x 30 cm, 50% CH3CN/H2O) to afford
0.81 g (k', 20) of the cis isomer. Bulb to bulb distillation (60 °C,
1
0.1 Torr) afforded 14 as a clear, colorless oil; H NMR (CDCl3):
d 1.30 (t, 3H, J = 7 Hz), 1.39 (t, 3H, J = 7 Hz), 4.24 (q, 2H, J = 7
Hz), 4.41 (q, 2H, J = 7Hz), 6.14 (s, 1H); 13C NMR (CDCl3): d
13.5, 13.5, 61.2, 63.7, 108.8 (q, C4, 3JCF = 3.5 Hz), 118.6 (CF3,
1JCF = 275 Hz), 137.7 (C3), 149.1 (q, C5, 2JCF = 36 Hz), 157.0,
161.8; 19F NMR (CDCl3): d -75.4; MS(EI) 317 (M+, 0.7), 272
(-OEt, 23), 139 (28), 115 (29), 87 (34), 69 (93), 62 (100); MS(CI)
318 (M+1, 100), 320 (A+2, 35).
Anal. Calcd. for C13H8F6ClNO3: C, 41.57; H, 2.08; N, 3.73.
Found: C, 41.74; H, 2.17; N, 3.74.
Methyl 3-(((4-(Trifluoromethyl)phenyl)(((4-(trifluoromethyl)-
phenyl)chloromethylene)-amino)methylene)amino)oxy-(4,4,4-
trifluoro)butenoate (9).
Anal. Calcd. for C10H11O5NClF3: C, 37.81; H, 3.49; N, 4.41.
Found: C, 37.75; H, 3.50; N, 4.35.
The more retained trans isomer (k', 26) was concentrated and
distilled bulb to bulb (60 °C, 0.1 Torr) to afford 0.27 g of 15 as
a clear, colorless oil; 1H NMR (CDCl3): d 1.32 (t,3H, 7 Hz),
1.41 (t,3H, 7 Hz), 4.26 (q 2H, 7 Hz), 4.43 (q,2H, 7Hz), 6.37
(s,1H); 13C NMR (CDCl3): d 14.0, 14.0, 61.7, 64.4, 105.4
Recrystallization of 9 from hexanes afforded a white, crys-
talline solid: mp 90.5-91.5 °C; 1H NMR (CDCl3): d 3.78 (s, 3H),
6.36 (s, 1H), 7.66-8.11 (m, 8H); 13C NMR (CDCl3): d 52.2
(CH3), 101.3 (C4), 119.0 (CF3, 1JCF = 276 Hz), 123.6 (CF3, 1JCF
1
3
(q,C4, JCF = 2.0 Hz), 118.5 (CF3, 1JCF = 273 Hz), 139.8 (C3),
= 273 Hz), 123.7 (CF32, JCF = 273 Hz), 125.7, 125.9, 128.3,
129.2, 131.1, 133.9 (q, JCF = 33 Hz), 134.0 (q, 2JCF = 33 Hz),
2
150.6 (q,C5, JCF = 38 Hz), 157.4 (C=O), 162.9 (C=O); 19F
2
134.1, 145.8, 152.7 (q, JCF = 37 Hz), 159.1, 164.2; 19F NMR
NMR (CDCl3): d -76.5; MS(EI) 317 (M+, 1), 272 (-OEt, 20),
139 (23), 115 (23), 87 (24), 69 (80), 62 (100); MS(CI) 318
(M+1, 100), 320 (A+2, 44).
(CDCl3): d -65.51 (s, 3F), -62.78 (s, 3F), -62.69 (s, 3F); MS(EI)
208 (32), 206 (CF3C6H4CNCl+, 100), 187 (19), 173 (35), 145
(CF3C6H4+, 61); MS(CI) 563 (M+1, 100).
Anal. Calcd. for C21H12N2O4ClF9: C, 44.82; H, 2.15; N, 4.98.
Found: C, 44.86; H, 2.16; N, 4.93.
Anal. Calcd. for C10H11O5NClF3: C, 37.81; H, 3.49; N, 4.41.
Found: C, 37.96; H, 3.54; N, 4.37.
Ethyl 5-(Pentafluoroethyl)-3-[4-(trifluoromethyl)phenyl]-4-isox-
azolecarboxylate (3b) and Ethyl 4-(Pentafluoroethyl)-3-[4-(tri-
fluoromethyl)phenyl]-5-isoxazolecarboxylate (4b).
Methyl 3-(((4-(Trifluoromethyl)phenyl)chloroethylene)amino)-
oxy-(4,4,4-trifluoro)butenoate (11).
A solution of 1 (13.1 g, 58.6 mmol) in 100 mL of CH2Cl2 was
cooled in a wet ice-acetone bath and treated with 2b (13.4 g, 62.0
mmol). To the cooled solution was subsequently added triethyl-
amine (9.0 mL, 64.6 mmol) dropwise and the solution stirred
overnight. The reaction was washed with 1 N HCl, dried and
concentrated in vacuo to afford a clear, orange-yellow oil. The oil
was purified by preparative chromatography (20% CH2Cl2 in
hexanes, 2” x 22” silica column) to yield two components; 8.93 g
(37.8%) of 3b (chromatographically unretained component) and
4.2 g (17.8%) of 4b (chromatographically retained component).
The major, less chromatographically retained component 3b was
evaporatively distilled and a small portion purified by chro-
matography (20% CH2Cl2 in hexanes) to afford an analytical
sample 3b: bp0.08 55-60 °C; HPLC(reverse phase a) tr=12.2 min;
1H NMR (CDCl3): d 1.30 (t, 3H, J = 7 Hz), 4.34 (q, 2H, J = 7
Hz), 7.76 (d, 2H, J = 8 Hz), 7.82 (d, 2H, J = 8 Hz); 13C NMR
A solution of 2.12 g (10.4 mmol) of oxime 10 in 20 mL of
methylene chloride was cooled in wet ice-acetone to –10 °C and
treated with 1.7 mL (1.98 g, 11.9 mmol) of 2a followed by 1.6 mL
(1.16 g, 11.5 mmol) of triethylamine. After stirring for a few min-
utes, the ice bath was removed and the mixture allowed to stir
overnight. The reaction mixture was treated with 1 N HCl,
extracted three times with CH2Cl2 and the combined extracts
dried and concentrated to afford 4.1 g of orange oil. The oil solid-
ified on standing and was recrystallized from methanol-water to
give 3.46 g (93.6%) of a slightly yellow, crystalline solid: mp
59 °C; 1H NMR (CDCl3): d 2.46 (s, 3H), 3.69 (s, 3H), 5.89
(s, 1H), 7.66 (d, 2H, J = 8.4 Hz), 7.78 (d, 2H, J = 8.4 Hz); 13C
NMR (CDCl3): d 13.5, 52.0, 103.0 (q, J = 4.0 Hz), 119.4 (q, CF3,
1
1JCF = 276 Hz), 123.9 (q, JCF = 272 Hz), 125.7 (q, J = 3.8 Hz),
127.1, 132.4 (q, 2JCF = 32.8 Hz), 137.8, 150.7 (q, 2JCF = 34.3 Hz),
160.0, 164.4; 19F NMR (CDCl3): d -64.0 (s, 3F), -70.5 (s, 3F).
Anal. Calcd. for C14H11NO3F6: C, 47.34; H, 3.12; N, 3.94.
Found: C, 47.46; H, 3.09; N, 3.97.
1
(CDCl3): d 13.7, 63.0, 108.6 (tq, CF2, JCF = 258 Hz, 2JCF = 42
1
2
Hz), 115.5 (C4), 118.2 (qt, CF3, JCF = 287 Hz, JCF = 36 Hz),
1
123.9 (CF3, JCF = 273 Hz), 125.8 (q, JCF = 4 Hz), 129.6,
Ethyl (Z,Z)-3-(((Carbethoxy)chloromethylene)amino)oxy-4,4,4-
trifluorobutenoate (14) and Ethyl (E,Z)-3-(((Carbethoxy)-
chloromethylene)amino)oxy-4,4,4-trifluorobutenoate (15).
130.2(C1), 133.0 (C4', 2JCF = 32 Hz), 158.8 (t, C5, 2JCF = 32 Hz),
159.4 (C3), 161.8; 19F NMR (CDCl3): d -62.8 (s, 3F), -83.0
(t, 3F, J = 3 Hz), -113.4 (q, 2F, J = 3 Hz); MS(EI) 403 (M+, 61),
375 (15), 358 (-OEt, 45), 284 (-CF2CF3, 42), 212 (100), 145
(CF3C6H4, 36); MS(CI) 404 (M+1, 100).
To a solution of 7.6 g (50 mmol) of ethyl chlorooximidoacetate
and 7.3 mL (8.32 g, 50 mmol) of ethyl 4,4,4-trifluoro-2-

Jul-Aug 2003
581
Reaction of Benzohydroximinoyl Chlorides and b-(Trifluoromethyl)acetylenic Esters
Anal. Calcd. for C15H9F8NO3: C, 44.68; H, 2.25; N, 3.56.
Found: C, 44.78; H, 2.23; N, 3.47.
nes and cooled to afford 19.0 g (76%) of 3d as a yellow, crys-
talline solid. A small sample was further recrystallized to give
off-white crystals 3d: mp 53-53.5 °C; 1H NMR (CDCl3): d 1.28
(t, 3H, J = 7 Hz), 4.33 (q, 2H, J = 7 Hz), 7.25 (t, 1H, 2JHF = 52
Hz), 7.73 (d, 2H, J = 8.5 Hz), 7.81 (d, 2H, J = 8.5 Hz); 13C NMR
(CDCl3): d 13.9, 62.4, 106.4 (t, CF2H, 1JCF = 241 Hz), 112.3 (t,
The minor component 4b was evaporatively distilled (55-70
°C, 60 mTorr) and the resultant oil dissoved in cold pentane to
afford a white, crystalline solid 4b: mp 35-36 °C; HPLC(reverse
phase a) tr=11.4 min; 1H NMR (CDCl3): d 1.44 (t, 3H, J=7 Hz),
4.52 (q, 2H, J=7 Hz), 7.64 (d, 2H, J=8 Hz), 7.75 (d, 2H, J=8 Hz);
C4, 3JCF = 5 Hz), 124.0 (q, CF3, 1JCF = 272 Hz), 125.4 (q, 3JCF
=
1
13C NMR (CDCl3): d 13.9, 63.8, 110.7(tq, CF2, JCF = 255 Hz,
3
4 Hz), 130.3, 130.8, 132.6 (q, C4', JCF = 33 Hz), 159.8 (C3),
161.8 (C=O), 166.7 (t, C5, 2JCF = 26 Hz); 19F NMR (CDCl3): d
-67.8 (s, 3F), -124.7 (d, 2H, 2JFH = 52 Hz).
2JCF = 42 Hz), 111.1 (t, C4, 2JCF = 30 Hz), 118.8 (qt, CF3, 1JCF
=
2
286 Hz, JCF = 38 Hz), 123.9 (q, CF3, 1JCF = 273 Hz), 125.6 (q,
2
3JCF = 4 Hz), 130.2, 130.6, 132.8 (q, C4', JCF = 32 Hz),
Anal. Calcd. for C14H10NO3F5: C, 50.16; H, 3.01; N, 4.18.
Found: C, 50.27; H, 3.06; N, 4.17.
155.4(C3), 161.8(two overlapping resonances, C5 and C=O);19
F
NMR (CDCl3): d -62.8 (s, 3F), -83.8 (t, 3F, J = 3 Hz), -105.9 (q,
2F, J = 3 Hz); MS(EI) 403 (M+, 27), 330 (-CO2Et, 100), 145
(CF3C6H4, 33); MS(CI) 404 (M+1, 100).
Anal. Calcd. for C15H9NO3F8: C, 44.68; H, 2.25; N, 3.47.
Found: C, 44.58; H, 2.30; N, 3.44.
The combined mother liquors from crystallization of the above
product were concentratedin vacuo and purified by chromatogra-
phy. Chromatographic separation of the regioisomers (silica, 21.2
mm i.d., 1% ethyl acetate in hexanes) afforded an additional 0.28
g of 3d and 0.56 g (2%) of 4d. Recrystallization from cold hexa-
1
nes gave a white, crystalline solid 4d: mp 51-52 °C; H NMR
Methyl 5-(Chlorodifluoromethyl)-3-[4-(trifluoromethyl)phenyl]-
4-isoxazolecarboxylate (3c).
(CDCl3): d 1.47 (t, 3H, J = 7 Hz), 4.53 (q, 2H, J = 7 Hz), 7.43 (t,
1H, 2JHF = 54 Hz), 7.76 (d, 2H, J = 8 Hz), 7.94 (d, 2H, J = 8 Hz);
13C NMR (CDCl3): d 14.1, 63.4, 108.8 (t, CF2H, 1JCF = 235 Hz),
117.4 (t, C4, 2JCF = 29 Hz), 123.8 (q, CF3, 1JCF = 272 Hz), 125.7
Purification by preparative chromatography (20% CH2Cl2 in
hexanes, 2” x 22” silica column) gave 14.42 g (68%) of a clear
oil. An analytical sample was prepared by crystallizing the oil in
a cold pentane solution. The crystalline solid was collected and
promptly melted upon reaching room temperature to afford a
clear, colorless oil: 1H NMR (CDCl3): d 3.89 (s,3H), 7.75 (d, 2H,
J = 8 Hz), 7.81 (d, 2H, J = 8 Hz); 13C NMR (CDCl3): d 53.1,
3
(q, 3JCF = 4 Hz), 129.5 (t, C5, JCF = 2 Hz),130.7, 132.6 (q, C4',
3
3JCF = 33 Hz), 156.1 (C4'), 159.4 (t, C3, JCF = 9 Hz), 161.0
(C=O); 19F NMR (CDCl3): d -67.8 (s, 3F), -115.2 (d, 2H, 2JFH
=
53 Hz); MS(EI) 335 (M +, 24), 262 (-CO2Et, 100), 145
(CF3C6H4+, 49); MS(DP/CI) 336 (M+1, 100).
1
1
111.0 (C4), 118.7 (-CF2Cl, JCF = 290 Hz), 123.9 (-CF3, JCF
=
=
Anal. Calcd. for C14H10NO3F5: C, 50.16; H, 3.01; N, 4.18.
Found: C, 50.12; H, 3.02; N, 4.10.
272 Hz), 125.7 (q, JCF = 4 Hz), 129.7, 130.3, 132.9 (C4', 2JCF
33 Hz), 159.9 (C3), 162.0 (C=O), 163.8 (C5, 2JCF = 36 Hz); 19F
NMR (CDCl3): d -51.6 (2F), -62.9 (3F); MS(EI) 355 (M+, 51, Cl1
cluster), 320 (-Cl, 16), 270 (-CF2Cl, 100), 211 (-CF2Cl,
-CO2CH3, 37), 145 (38), 59 (45); MS(CI) 356 (M+1, 100, Cl1
cluster).
5-(Trifluoromethyl-3-[4-(trifluoromethyl)phenyl]isoxazole (3e).
To a round bottom flask equipped with a dry ice condensor was
added 100 mL of methylene chloride. The liquid was cooled to
-10 °C, the condensor charged with dry ice-acetone and a gas
inlet tube was used to add 8.24 g (87.7 mmol) of trifluoro-
propyne. The ice bath was removed and the solution reached
10 °C at which time the trifluoropropyne began to reflux. To this
solution was added 13.6 g (60.7 mmol) of 1 and the nearly homo-
geneous solution treated with 8.5 mL (61 mmol) of triethylamine.
After stirring overnight at room temperature, the mixture was
washed with 1 N HCl, dried and the solvent removed to give a
Anal. Calcd. for C13H7O3ClF5N: C, 43.90; H, 1.98; N, 3.94.
Found: C, 44.01; H, 1.99; N, 3.94.
Methyl 4-(Chlorodifluoromethyl)-3-[4-(trifluoromethyl)phenyl]-
5-isoxazolecarboxylate (4c).
The more retained chromatographic fraction was concentrated
to afford 1.3 g (5%) of 4c as a clear, colorless oil: n22 1.4834;
D
1H NMR (CDCl3): d 4.07 (s, 3H), 7.70 -7.80 (m, 4H); 13C NMR
crude oil which crystallized overnight. By H NMR, the crude
1
2
1
(CDCl3): d 53.8, 119.0 (t, JCF = 33 Hz), 120.7 (t, JCF = 290
material appears to contain 23% of the 4-CF3 isomer and 77% of
the desired 5-CF3 isomer. Recrystallization from cold methanol
1
Hz), 123.7 (q, JCF = 273 Hz), 125.6 (q, J = 4 Hz), 129.7, 129.7,
130.3, 132.7 (q, 2JCF = 33 Hz), 155.8, 158.6 (t, J = 3 Hz), 159.8;
19F NMR (CDCl3): d -45.6(s, 2F), -65.0 (s, 3F); MS(EI) 355
(M+, 43, Cl1 cluster), 296 (100), 206 (91), 145 (60).
Anal. Calcd. for C13H7O3ClF5N: C, 43.90; H, 1.98; N, 3.94.
Found: C, 44.00; H, 2.02; N, 3.98.
afforded 7.0 g (41%) of 3e as a white solid: mp 49-54 °C; H
1
4
NMR (CDCl3): d 7.06 (q, 1H, JHF = 0.9 Hz), 7.74 (d, 2H, J = 8
Hz), 7.93 (d, 2H, J = 8 Hz); 13C NMR (CDCl3): d 103.6 (q, C4,
1
1
2JCF = 2 Hz), 118.0 (CF3, JCF = 270 Hz), 123.9 (CF3, JCF
=
272 Hz), 126.4 (q, 3JCF = 4 Hz), 127.5, 131.0, 133.0 (q, 2JCF = 33
Hz), 160.1 (C5, 2JCF = 43 Hz), 161.7 (C3); 19F NMR (CDCl3): d
-67.9, -69.1.
5-(Difluoromethyl)-3-[4-(trifluoromethyl)phenyl]-4-isoxazole-
carboxylic Acid, Ethyl Ester (3d) and 4-(Difluoromethyl)-3-[4-
(trifluoromethyl)phenyl]-5-isoxazolecarboxylic Acid, Ethyl
Ester (4d).
Anal. Calcd. for C11H5NOF6: C, 46.99; H, 1.79; N, 4.98.
Found: C, 47.27; H, 1.86; N, 5.19.
4,5-Bis(trifluoromethyl)-3-(4-trifluoromethyl)phenylisoxazole
(3f).
To a solution of 1 (16.8 g, 75 mmol) in 100 mL of methylene
chloride warmed to 30 °C was added 2d (11.2 g, 76 mmol). The
stirred mixture was treated dropwise with triethylamine
(11.5 mL, 83 mmol) and the temperature kept between 32-42 °C
with the aid of a cold water bath. After 2 hours, the mixture was
washed with 1 N HCl, dried and concentratedin vacuo to afford a
crude orange oil. The oil was dissolved in 50 mL of warm hexa-
A solution of 7.31 g (45 mmol) of hexafluoro-2-butyne in 100
mL of CH2Cl2 was prepared in a vessel cooled with a dry ice-
acetone bath and equipped with a dry ice-acetone condensor. The
cold solution was treated with 10.1 g (45 mmol) of 1, allowed to
warm to room temperature and treated dropwise with 6.3 mL

582
B. C. Hamper and K. L. Leschinsky
Vol. 40
(45 mmol) of triethylamine. Total addition time was 15 minutes.
After addition was complete, the acetylene no longer refluxed in
the apparatus. The mixture was washed with 1 N HCl, dried and
the solvent removed to afford 13.3 g of a crude oil. Bulb to bulb
distillation (45-60 °C, 0.1 Torr) afforded 9.44 g (60%) of 3f as a
clear, colorless oil; 1H NMR (CDCl3): d 7.78 (m); 13C NMR
The concentrated mother liquors from crystallization of 17
were purified by chromatography (2” x 22”, silica, 20% CH2Cl2)
to afford an additional 0.75 g of 17 (k' = 1.7, total yield of 26%)
and 2.58 g (k' = 5.0) of 16 (28%). Recrystallization from hexanes
gave an analytical sample of 16 as a white, crystalline solid: mp
114.0-114.5 °C (lit.[35] 114-116 °C); 1H NMR (CDCl3): d 7.64-
2
3
(CDCl3): d 111.6 (qq, C4, JCF = 41 Hz, JCF = 2 Hz), 117.3
7.70 (m, 8H); 13C NMR (CDCl3): d 113.2, 123.6 (q, CF3, 1JCF
=
1
1
1
3
(CF3, JCF = 274 Hz), 120.0 (CF3, JCF = 269 Hz), 123.8 (CF3,
1JCF = 272 Hz), 126.2 (q, 3JC2F = 4 Hz), 129.4, 129.7, 133.6 (q,
2JCF = 33 Hz), 159.6 (qq, C5, JCF = 44 Hz, 3JCF = 3 Hz), 161.1
(q, C3, JCF = 1.3 Hz); 19F NMR (CDCl3): d -54.96 (q, 7 Hz),
-62.02 (q, 7Hz), -63.14 (s); MS(CI) 350 (M+1, 100); MS(EI) 349
(M+,49), 330 (-F,28), 280 (-CF3,100), 145 (72).
273 Hz), 123.6 (CF3, JCF = 273 Hz), 126.3 (q, JCF = 4 Hz),
3
126.4 (q, JCF = 4 Hz), 129.0, 129.2, 129.9, 129.9, 130.0, 132.8
(2JCF = 33 Hz), 133.3 (2JCF = 33 Hz), 155.0; 19F NMR (CDCl3):
d -68.0, -68.1; MS(EI) 374 (M+, 7), 314 (-N2O2, 100); MS(CI)
375 (M+1, 100).
Anal. Calcd. for C16H8N2O2F6: C, 51.35; H, 2.15; N, 7.49.
Found: C, 51.41; H, 2.16; N, 7.43.
Anal. Calcd. for C12H4ONF9: C, 41.28; H, 1.15; N, 4.01.
Found: C, 41.37; H, 1.15; N, 4.00.
Acknowledgments.
5-Phenyl-4-trifluoromethyl-3-(4-trifluoromethyl)phenylisoxa-
zole (4g).
The authors wish to thank Dr. Lawrence H. Brannigan for pro-
viding compound 12 and a comparison sample of diethyl furox-
andicarboxylate 13.
To a solution of 4.5 g (20 mmol) of 1 and 2.37 g (22.1 mmol)
of (3,3,3-trifluoro-1-propynyl)benzene 2g in 40 mL of methylene
chloride at room temperature was added 3.1 mL (22.2 mmol) of
triethylamine. After stirring overnight, the mixture was washed
with 1 N HCl, dried and the solvent removed to afford 5.4 g of an
oily, brownish solid. Analysis by 19F NMR shows a mixture of
nearly equimolar amounts of oxadiazole 17, furoxan 16 and a
desired isoxazole product. Removal of the furoxan was achieved
by chromatography (silica, 2” x 22”, 20% CH2Cl2 in hexanes) to
afford 1.66 g (k', 1.1) of a mixture of products and 0.82 g (k', 3.5)
of furoxan. The less retained material was further purified (C-18,
21.2 mmi.d. x 30 cm, 80% CH3CN/H2O) to give 0.78 g of oxadi-
azole (k', 8.5) and 0.77 g (11%) of 4g (k', 4.1). Recrystallization
from cold hexanes afforded 4g as a white, crystalline solid: mp
REFERENCES AND NOTES
*
Current Address: Bruce C. Hamper, Pfizer Corporation, 700
Chesterfield Parkway West, Chesterfield, MO 63017.
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1489 (1997); X. Q. Tang and C. M. Hu, J. Fluorine Chem., 73, 133
(1995).
[13] W. Peng, S. Zhu and G. Jin, Tetrahedron, 57, 5781(2001).
[14] P. Bravo, D. Diliddo and G. Resnati, Tetrahedron, 50, 8827
(1994); P. Bravo, D. Diliddo and G. Resnati, Heterocycles, 34, 1703
(1992).
[15] Y. Shen, J. Zheny and Y. Huang, Synthesis, 970 (1985).
[16] D. R. Brittelli and G. A. Boswell, J. Org. Chem., 46, 316
(1981).
1
86.5 °C; H NMR (CDCl3): d 7.53 (m, 3H), 7.77 (m, 6H); 13C
2
NMR (CDCl3): d 106.5 (C4, JCF = 38 Hz), 121.8 (CF3, 1JCF
=
1
3
268 Hz), 124.0 (CF3, JCF = 282 Hz), 125.7 (q, JCF = 4 Hz),
128.8, 128.9, 129.0, 129.4, 131.4, 131.9, 132.5 (q, C1', 2JCF = 33
Hz), 160.7 (C3), 171.9 (q, C5, JCF = 3 Hz); 19F NMR (CDCl3):
3
d -53.21 (s), -62.63 (s).
Anal. Calcd. for C17H9ONF6: C, 57.15; H, 2.54; N, 3.92.
Found: C, 57.23; H, 2.57; N, 3.88.
3,5-Bis[4-(trifluoromethyl)phenyl-1,2,4-oxadiazole (17) and 3,4-
Bis[4-(trifluoromethyl)phenyl]furoxan (16).
A solution of 4.8 g (25 mmol) of 4-trifluoromethylbenzalde-
hyde oxime in 75 mL of methylene chloride was heated to
reflux and treated with 7.6 mL (54 mmol) of triethylamine.
After two hours, the mixture was cooled and washed with 1 N
HCl, dried and concentrated in vacuo to afford 10.1 g of a crude
brownish residue. The residue was triturated with cold
methanol to give a white, crystalline solid. Recrystallization
from methanol afforded 1.5 g of 17 as analytical material: mp
1
121-122 °C; H NMR (CDCl3): d 7.74 (d, 2H, 8 Hz), 7.80 (d,
2H, 8 Hz), 8.25 (d, 2H, 8 Hz), 8.29 (d, 2H, 8 Hz); 13C NMR
1
1
(CDCl3): d 123.6 (q, CF3, JCF = 273 Hz), 123.8 (CF3, JCF
=
273 Hz), 126.0 (q, JCF = 4 Hz), 126.3 (q, 3JCF = 4 Hz), 127.2,
3
2
127.9, 128.6, 130.0, 133.2 (C1', JCF = 33 Hz), 134.6 (C1',
2JCF = 33 Hz), 168.3 (C4), 174.9 (C5); 19F NMR (CDCl3): d
-68.0, -68.2; MS(EI) 358 (M+, 43), 187 (CF3C6H4CNO+, 100);
MS(CI) 359 (M+1, 100).
[17] For a general reference for preparation of trifluoromethyla-
zoles, see: J. Elguero, A. Fruchier, N. Jagerovic and A. Werner, Organic
Prep. Proc. Int., 27, 33 (1995).
Anal. Calcd. for C16H8N2OF6: C, 53.64; H, 2.25; N, 7.82.
Found: C, 53.50; H, 2.29; N, 7.77.

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Reaction of Benzohydroximinoyl Chlorides and b-(Trifluoromethyl)acetylenic Esters
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Washington, DC, 1995, pg. 114-121.
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3275 (1973).
13
[28] For a similar analysis of CF substituted pyrazoles by
C
3
NMR, see: B. C. Hamper, M. L. Kurtzweil and J. P. Beck, J. Org. Chem.,
57, 5680 (1992).
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